Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by a distinct deposition of an abnormal form of the tau protein in a pattern that is unique from other diseases, including Alzheimer's disease (AD). CTE has been found most often in professional contact sport athletes (e.g., boxing, football) who have been subjected to repetitive blows to the head resulting in concussive and subconcussive trauma. Neuropathologically-confirmed CTE has been reported in individuals as young as 17 and in athletes who only played sports through high school or college. It also has been found in non-athletes who experienced repetitive head impacts, including epileptics, victims of physical abuse, and military service members. In contrast to what may be inferred by the extensive media attention on CTE, the science of CTE remains in its infancy; critical questions remain, such as whether or not it is a common disease. Although the neuropathological features of CTE have become further clarified in recent years, the clinical presentation of CTE is still not well characterized, even though there have been case reports in the literature of dementia pugilistica in boxers since the early 1900's. Clinical diagnostic criteria have only recently been published and lack validation. Neuroimaging and fluid biomarkers developed for the diagnosis of other neurodegenerative diseases have only been used in preliminary studies. There is thus an urgent need to develop accurate methods for detecting and diagnosing CTE during life so that effective interventions for prevention and treatment can be developed. Moreover, though a history of repetitive head impacts is a necessary risk factor for CTE, it alone is not sufficient. There is a need to understand what specific aspects of the head impact exposure places an individual at increased risk for CTE and to examine potential genetic modifiers of that risk. To address these needs, we propose a multidisciplinary, multicenter, longitudinal study of former athletes with high exposure to repetitive head impacts (120 former NFL players with and without symptoms) or medium exposure to repetitive head impact (60 former college football players with and without symptoms) and a control group of 60 asymptomatic same-age men without any history of repetitive head impact exposure or traumatic brain injury. The aims of our proposal are: (1) to collect and analyze neuroimaging and fluid biomarkers for the detection of CTE during life, including the use of a novel PET tracer to measure the amount of abnormal brain tau; (2) to characterize the clinical presentation of CTE; (3) to examine the progression of CTE over a three year period; (4) to refine and validate diagnostic criteria for the clinical diagnosisof CTE; (5) to investigate genetic and head impact exposure risk factors for CTE; and (6) to share project data with researchers across the country and abroad in order to expedite growth in our understanding and treatment of this disease.